In Vivo Analysis of TrkB Signaling During Sympathetic Nervous System Development and Neuroblastoma Pathogenesis

Stowers Institute For Medical Research, Kansas City MO

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Abstract

? DESCRIPTION (provided by applicant): The molecular and cellular interactions that orchestrate the patterning of the vertebrate peripheral nervous system have yet to be fully elucidated. Upon delamination from the neural tube, trunk neural crest cells destined to form the vertebral chain of sympathetic ganglia migrate ventrally to the vicinity of the dorsal aorta where they aggregate and condense to form the primary chain of sympathetic ganglia composed of differentiated sympathetic neurons and precursor cells. Failure of the neural crest cells to properly migrate and differentiate may result in birth defects and lead to neuroblastoma, a pediatric tumor. of the peripheral nervous system that arises from sympatho-adrenal lineages of the neural crest. Unfortunately, the lack of information about normal development of the sympathetic nervous system and how mis-regulation of signals transform the normal neuroblast to neuroblastoma has severely limited early neuroblastoma detection and treatment, making this disease often fatal in infants. We propose to study sympathetic nervous system development and neuroblastoma pathogenesis using state- of-the-art in vivo imaging in living avian embryos. We discovered a novel role for TrkB signaling during sympathetic neurogenesis, which strikingly has recently been associated with aggressive neuroblastomas. We hypothesize that TrkB signals regulate the plasticity and invasive ability of the neural crest during sympathetic nervous system development at a critical time period when the early transformation from normal neuroblast to neuroblastoma occurs. To test this hypothesis we will determine the functional role of TrkB signaling in sympathetic nervous system development and develop a quail embryo model for neuroblastoma pathogenesis. Quail embryos allow transplantation and visualization of individual human neuroblastoma cell behaviors, a technique pioneered in our laboratory. We recently discovered that human neuroblastoma cells transplanted into the avian embryo follow host neural crest pathways and do not form tumors. The success of this proposal will have a direct impact on neural development and neuroblastoma cancer by providing: (i) critical information on the in vivo role of TrkB signaling during sympathetic neurogenesis and in the early transition from normal neuroblast to neuroblastoma; (ii) an in vivo model to rapidly assay the plasticity and invasiveness of neuroblastoma cells and response to potential inhibitors.